Controlled release metformin compositions

ABSTRACT

A composition for treating patients having non-insulin-dependent diabetes mellitus (NIDDM) by administering a controlled release oral solid dosage form containing preferably a biguanide drug such as metformin, on a once-a-day basis. The dosage form provides a mean time to maximum plasma concentration (T max ) of the drug which occurs at 5.5 to 7.5 hours after oral administration on a once-a-day basis to human patients. Preferably, the dose of drug is administered at dinnertime to a patient in the fed state.

BACKGROUND OF THE INVENTION

The present invention relates to controlled release unit doseformulations containing an antihyperglycemic drug. More specifically,the present invention relates to an oral dosage form comprising abiguanide such as metformin or buformin or a pharmaceutically acceptablesalt thereof such as metformin hydrochloride or the metformin saltsdescribed in U.S. Pat. Nos. 3,957,853 and 4,080,472 which areincorporated herein by reference.

In the prior art, many techniques have been used to provide controlledand extended-release pharmaceutical dosage forms in order to maintaintherapeutic serum levels of medicaments and to minimize the effects ofmissed doses of drugs caused by a lack of patient compliance.

In the prior art are extended release tablets which have an osmoticallyactive drug core surrounded by a semipermeable membrane. These tabletsfunction by allowing a fluid such as gastric or intestinal fluid topermeate the coating membrane and dissolve the active ingredient so itcan be released through a passageway in the coating membrane or if theactive ingredient is insoluble in the permeating fluid, pushed throughthe passageway by an expanding agent such as a hydrogel. Somerepresentative examples of these osmotic tablet systems can be found inU.S. Pat. Nos. 3,845,770, 3,916,899, 4,034,758, 4,077,407 and 4,783,337.U.S. Pat. No. 3,952,741 teaches an osmotic device wherein the activeagent is released from a core surrounded by a semipermeable membraneonly after sufficient pressure has developed within the membrane toburst or rupture the membrane at a weak portion of the membrane.

The basic osmotic device described in the above cited patents have beenrefined over time in an effort to provide greater control of the releaseof the active ingredient. For example U.S. Pat. Nos. 4,777,049 and4,851,229 describe an osmotic dosage form comprising a semipermeablewall surrounding a core. The core contains an active ingredient and amodulating agent wherein the modulating agent causes the activeingredient to be released through a passageway in the semipermeablemembrane in a pulsed manner. Further refinements have includedmodifications to the semipermeable membrane surrounding the active coresuch as varying the proportions of the components that form themembrane; i.e., U.S. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625 orincreasing the number of coatings surrounding the active core; i.e.,U.S. Pat. Nos. 5,650,170 and 4,892,739.

Although vast amounts of research has been performed on controlled orsustained release compositions and in particular on osmotic dosageforms, very little research has been performed in the area of controlledor sustained release compositions that employ antihyperglycemic drugs.

Metformin is an oral antihyperglycemic drug used in the management ofnon-insulin-dependent diabetes mellitus (NIDDM). It is not chemically orpharmacologically related to oral sulfonylureas. Metformin improvesglucose tolerance in NIDDM patients by lowering both basal andpostprandial plasma glucose. Metformin hydrochloride is currentlymarketed as GLUCOPHAGE® tablets by Bristol-Myers Squibb Co. EachGLUCOPHAGE® tablet contains 500, 850 or 1000 mg of metforminhydrochloride. There is no fixed dosage regimen for the management ofhyperglycemia in diabetes mellitus with GLUCOPHAGE®. Dosage ofGLUCOPHAGE® is individualized on the basis of both effectiveness andtolerance, while not exceeding the maximum recommended dose of 2550 mgper day.

Metformin has been widely prescribed for lowering blood glucose inpatients with NIDDM. However, being a short acting drug, metforminrequires twice-daily (b.i.d.) or three-times-a-day (t.i.d.) dosing.Adverse events associated with metformin use are often gastrointestinalin nature (e.g., anorexia, nausea, vomiting and occasionally diarrhea,etc.). These adverse events may be partially avoided by either reducingthe initial and/or maintenance dose or using an extended-release dosageform. Another clear advantage of an extended release dosage form is areduction in the frequency of administration. All of these findingssuggest that an extended-release dosage form of metformin may improvethe quality of therapy in patients with NIDDM and the safety profilerelative to a conventional dosage form.

The limited work on controlled or sustained release formulations thatemploy antihyperglycemic drugs such as metformin hydrochloride includesthe combination of the antihyperglycemic drug and an expanding orgelling agent to control the release of the drug from the dosage form.This research is exemplified by the teachings of WO 96/08243 and by theGLUCOPHAGE® metformin HCl product.

It is reported in the 50^(th) Edition of the Physicians' Desk Reference,copyright 1996, p. 753, that food decreases the extent and slightlydelays the absorption of metformin delivered by the GLUCOPHAGE® dosageform. This decrease is shown by approximately a 40% lower peakconcentration, a 25% lower bioavailability and a 35-minute prolongationof time to peak plasma concentration following administration of asingle GLUCOPHAGE® tablet containing 850 mg of metformin HCl with foodcompared to the similar tablet administered under fasting conditions.

A controlled release metformin dosage form is also described in WO99/47128. This reference describes a controlled release delivery systemfor metformin which includes an inner solid particulate phase formed ofsubstantially uniform granules containing metformin and one or morehydrophilic polymers, one or more hydrophobic polymers and one or morehydrophobic materials, and an outer continuous phase in which the abovegranules are embedded and dispersed throughout. The outer continuousphase includes one or more hydrophilic polymers, one or more hydrophobicpolymers and one or more hydrophobic materials.

Our own WO 99/47125 discloses controlled release metformin formulationsproviding a Tmax from 8 to 12 hours.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a controlled orsustained release of an antihyperglycemic drug which provides effectivecontrol of blood glucose levels in humans.

It is a further object of the present invention to provide a method oftreating human patients with non-insulin-dependent diabetes mellitus(NIDDM) on a once-a-day basis with an antihyperglycemic drug whichprovides effective control of blood glucose levels in humans.

It is a further object of the present invention to provide formulationsfor treating human patients with non-insulin-dependent diabetes mellitus(NIDDM) which provides advantages over the state-of-the-art, and whichmay be administered on a once-a-day basis by itself or together withother antidiabetic agents, and methods thereof.

It is a further object of the present invention to provide a controlledor sustained release formulation of an antihyperglycemic drug whereinthe bioavailability of the drug is not decreased by the presence offood.

It is a further object of the present invention to provide a controlledor sustained release formulation of an antihyperglycemic drug that doesnot employ an expanding polymer.

It is also a further object of the present invention to provide acontrolled or sustained release formulation of an antihyperglycemic drugthat can provide continuous and non-pulsating therapeutic levels of thedrug to an animal or human in need of such treatment over a twelve hourto twenty-four hour period.

It is an additional object of other embodiments of the present inventionto provide a controlled or sustained release formulation for anantihyperglycemic drug that obtains peak plasma levels from 5.5 to 7.5hours after administration under various conditions. Alternatively, thetime to peak plasma levels are from 6.0 to 7.0, from 5.5 to 7.0 or from6.0 to 7.5.

It is also an object of this invention to provide a controlled orsustained release pharmaceutical formulation having a homogeneous corewherein the core component may be made using ordinary tablet compressiontechniques.

In accordance with the above-mentioned objects and others, the presentinvention provides a controlled release oral dosage form comprising anantihyperglycemic drug, preferably a biguanide (e.g., metformin or apharmaceutically acceptable salt thereof) that is suitable for providingonce-a-day administration of the drug, wherein the dosage form providesa mean time to maximum plasma concentration (T_(max)) of the drug from5.5 to 7.5 hours after administration. The dosage form comprises thedrug and a membrane. In certain preferred embodiments, the dosage formcomprises a tablet.

In preferred embodiments, the controlled release oral dosage form of thepresent invention is a tablet comprising:

-   -   (a) a core comprising:        -   (i) the antihyperglycemic drug;        -   (ii) optionally a binding agent; and        -   (iii) optionally an absorption enhancer;    -   (b) a membrane coating surrounding the core; and    -   (c) at least one passageway in the membrane.

When the drug is metformin or a pharmaceutically acceptable salt thereofand is administered on a once-a-day basis, the daily dose may vary,e.g., from about 500 mg to about 2500 mg. Such daily dose may becontained in one controlled-release dosage form of the invention, or maybe contained in more than one such dosage form. For example, acontrolled-release metformin dosage form may be formulated to containabout 1000 mg of the drug, and two of said dosage form may beadministered together to provide once-a-day metformin therapy. The dailydose of the drug (i.e. metformin or pharmaceutically acceptable saltthereof) may range from about 500 mg to about 2500 mg, from about 1000mg to about 2500 mg, or from about 2000 mg to about 2500 mg, dependingon the clinical needs of the patient.

In certain preferred embodiments, the controlled release solid oraldosage form of the present invention provides a width at 50% of theheight of a mean plasma concentration/time curve of the drug (e.g., ofmetformin) from about 4.5 to about 13 hours, more preferably from about5.5 to about 10 hours, more preferably from about 6 to about 8 hours.

In certain embodiments, the controlled release oral dosage form of thepresent invention provides a mean maximum plasma concentration (C_(max))of the antihyperglycemic drug which is more than about seven times themean plasma level of said drug at about 24 hours after administration.In preferred embodiments, the controlled release oral dosage form of thepresent invention provides a mean maximum plasma concentration (C_(max))of the drug which is from about 7 times to about 14 times the plasmalevel of the drug at about 24 hours after the administration, morepreferably from about 8 times to about 12 times the plasma level of thedrug at about 24 hours after administration.

In certain embodiments of the present invention, when the drug ismetformin or a pharmaceutically acceptable salt thereof, the controlledrelease oral dosage form provides a mean maximum plasma concentration(C_(max)) of the drug that is about 1500 ng/ml to about 3000 ng/ml,based on administration of a 2000 mg once-a-day dose of metformin, morepreferably about 1700 ng/ml to about 2000 ng/ml, based on administrationof a 2000 mg once-a-day dose of metformin.

In certain embodiments of the present invention, when the drug ismetformin or a pharmaceutically acceptable salt thereof, the controlledrelease dosage form provides a mean AUC_(0-24hr) that is about 17200ng.hr/ml to about 33900 ng.hr/ml, based on administration of a 2000 mgonce-a-day dose of metformin; preferably about 17200 ng.hr/ml to about26500 ng.hr/ml, based on administration of a 2000 mg once-a-day dose ofmetformin; more preferably about 19800 ng.hr/ml to about 33900 ng.hr/ml,based on administration of a 2000 mg once-a-day dose of metformin.

In certain embodiments of the invention, the administration of theantihyperglycemic drug, e.g., at least one metformin dosage formprovides a mean AUC_(0-24hr) from at least 80%, preferably at least 90%of the mean AUC₀₋₂₄ provided by administration of the reference standard(GLUCOPHAGE) twice a day, wherein the daily dose of the referencestandard is equal to the once-a day dose of metformin administered inthe controlled release oral dosage form of the present invention.

In certain embodiments of the present invention, the controlled releasedosage form exhibits the following dissolution profiles of theantihyperglycemic drug (e.g., metformin) when tested in a USP type 2apparatus at 75 rpm in 900 ml of simulated intestinal gastric fluid (pH7.5 phosphate buffer) at 37° C.: 0-30% of the drug released after 2hours; 10-45% of the drug released after 4 hours; 30-90% of the drugreleased after 8 hours; not less than 50% of the drug released after 12hours; not less than 60% of the drug released after 16 hours; and notless than 70% of the drug released after 20 hours.

In certain preferred embodiments, the controlled release solid oraldosage form exhibits the following dissolution profiles when tested inUSP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal gastricfluid (pH 7.5 phosphate buffer) at 37° C.: 0-25% of the drug (e.g.,metformin or a pharmaceutically acceptable salt thereof) released after2 hours; 20-40% of the drug released after 4 hours; 45-90% of the drugreleased after 8 hours; not less than 60% of the drug released after 12hours; not less than 70% of the drug released after 16 hours; and notless than 80% of the drug released after 20 hours.

With respect to embodiments of the present invention where theantihyperglycemic drug is metformin, it has been found that drugs suchas metformin provide substantially linear pharmacokinetics up to a levelof about 2 grams per day. Therefore, it is contemplated for purposes ofthe present invention that a given plasma level (e.g., C_(max)) ofmetformin per specified dose will be directly proportional to otherdoses of metformin. Such proportional doses and plasma levels arecontemplated to be within the scope of the invention and to be withinthe scope of the appended claims.

The dosage form of the present invention can provide therapeutic levelsof the antihyperglycemic drug for twelve to twenty-four hour periods anddoes not exhibit a decrease in bioavailability if taken with food. Infact, a slight increase in the bioavailability of the antihyperglycemicdrug is observed when the controlled release dosage form of the presentinvention is administered with food. In a preferred embodiment, thedosage form can be administered once-a-day, ideally with or after ameal, preferably with or after the evening meal, and providestherapeutic levels of the drug throughout the day with peak plasmalevels being obtained between 5.5 to 7.5 hours after administration.

The present invention is also directed to a method of lowering bloodglucose levels in human patients needing treatment fornon-insulin-dependent diabetes mellitus (NIDDM), comprising orallyadministering to human patients on a once-a-day basis a dose of a drugcomprising a biguanide (e.g., metformin or a pharmaceutically acceptablesalt thereof), said drug being contained in at least one solid oralcontrolled release dosage form of the present invention. When the drugis metformin, the daily dose of the drug may be from about 500 mg toabout 2500 mg, from about 1000 mg to about 2500 mg, or from about 2000mg to about 2500 mg, depending on the clinical needs of the patient.

The controlled release dosage form of the present invention provides adelayed T_(max), as compared to the T_(max) provided by GLUCOPHAGE. Thedelayed T_(max) occurs from 5.5 to 7.5 hours after administration. Ifthe drug (e.g., metformin) is administered at dinner time, the T_(max)would occur during the time when gluconeogenesis is usually at itshighest (e.g., around 2 a.m.).

The present invention also includes a method of treating patients withNIDDM comprising orally administering to human patients on a once-a-daybasis a dose of a drug comprising a biguanide (e.g., metformin or apharmaceutically acceptable salt thereof), contained in at least oneoral controlled release dosage form of the present invention. When thedrug is metformin, the daily dose of the drug may be from about 500 mgto about 2500 mg, from about 1000 mg to about 2500 mg, or from about2000 mg to about 2500 mg, depending on the clinical needs of thepatient. In certain embodiments, the method of treatment according tothe present invention involves once-per-day metformin monotherapy as anadjunct to diet to lower blood glucose in patients with NIDDM whosehyperglycemia may not be satisfactorily managed on diet alone. Incertain other embodiments, the once-a-day metformin therapy of thepresent invention may be used concomitantly with a sulfonylurea, e.g.,when diet and monotherapy with a sulfonylurea alone do not result inadequate glycemic control. In certain other embodiments, the once-a-daymetformin therapy of the present invention may be used concomitantlywith a glitazone, e.g., when diet and monotherapy with a glitazone alonedo not result in adequate glycemic control.

The present invention is further directed to a method of controlling theserum glucose concentration in human patients with NIDDM, comprisingadministering to patients having NIDDM on a once-a-day basis, preferablyat dinner time, an effective dose of a biguanide (e.g., metformin)contained in at least one oral controlled release dosage form of thepresent invention.

The present invention further includes a controlled-release dosage formof a drug comprising a biguanide (e.g., metformin) suitable foronce-a-day administration to human patients with NIDDM, the dosage formcomprising an effective amount of the drug to control blood glucoselevels for up to about 24 hours and an effective amount of acontrolled-release carrier to provide controlled release of the drugwith a mean time to maximum plasma concentration (T_(max)) of the drugfrom 5.5 to 7.5 hours after administration and a width at 50% of theheight of a mean plasma concentration/time curve of the drug from about6 to about 13 hours. In preferred embodiments, the administration of thecontrolled-release dosage form occurs at fed state, more preferably atdinner time.

In certain preferred embodiments, the controlled-release dose of thedrug (e.g., metformin or a pharmaceutically acceptable salt thereof)according to the present invention is provided by one or more of acontrolled-release tablet comprising

-   -   (a) a core comprising:        -   (i) the antihyperglycemic drug (e.g., metformin or a            pharmaceutically acceptable salt thereof);        -   (ii) optionally a binding agent; and        -   (iii) optionally an absorption enhancer;    -   (b) a membrane coating surrounding the core; and    -   (c) at least one passageway in the membrane.

In certain preferred embodiments, the mean time to maximum plasmaconcentration of the drug is reached from 6.5 to 7.5 hours afteradministration at dinner time.

In certain embodiments of the invention when the drug is a biguanide(e.g. metformin or a pharmaceutically acceptable salt thereof), thecontrolled release dosage form provides upon single administration, ahigher mean fluctuation index in the plasma than an equivalent dose ofan immediate release composition administered as two equal divideddoses, one divided dose at the start of the dosing interval and theother divided dose administered 12 hours later, preferably maintainingbioavailability from at least 80% preferably from at least 90% of theimmediate release composition.

In certain embodiments of the present invention, the mean fluctuationindex of the dosage form is from about 1 to about 4, preferably about 2to about 3, more preferably about 2.5.

In certain embodiments of the invention which exhibit a higher meanfluctuation index in the plasma than an equivalent dose of an immediaterelease composition administered as two equal divided doses, the ratioof the mean fluctuation index between the dosage form and the immediaterelease composition is about 3:1, preferably about 2:1, more preferably1.5:1.

When the drug is metformin or a pharmaceutically acceptable saltthereof, the doses of drug which exhibit the above disclosed meanfluctuation indexes can be any effective dose administered to a patientwith NIDDM for the reduction of serum glucose levels. For example, thedose can from about 500 mg to about 2500 mg, from about 1000 mg to about2000 mg or from about 850 mg to about 1700 mg metformin orpharmaceutically acceptable salt thereof.

The drugs which may used in conjunction with the present inventioninclude those drugs which are useful for the treatment ofnon-insulin-dependent diabetes mellitus (NIDDM), including but notlimited to biguinides such as metformin or buformin or pharmaceuticallyacceptable salts thereof. When the drug used in the present invention ismetformin, it is preferred that the metformin be present in a salt form,preferably as metformin hydrochloride.

The term “metformin” as it is used herein means metformin base or anypharmaceutically acceptable salt e.g., metformin hydrochloride.

The term “dosage form” as it is used herein means at least one unitdosage form of the present invention (e.g. the daily dose of theantihyperglycemic agent can be contained in 2 unit dosage forms of thepresent invention for single once-a-day administration).

The term “morning” as it is used herein with respect to the dosing ofthe controlled release formulations of the invention means that thecontrolled release formulation is orally administered early in the dayafter the patient has awakened from overnight sleep, generally betweenabout 6 a.m. and 11 a.m. (regardless of whether breakfast is eaten atthat time, unless so specified herein).

The term “dinnertime” or “at dinner” as it is used herein with respectto the dosing of the controlled release formulations of the inventionmeans that the controlled release formulation is orally administered ata time when dinner is normally eaten (regardless of whether a meal isactually eaten at that time, unless so specified herein), generallybetween about 4 p.m. and 8 p.m.

The term “bedtime” as it is used herein with respect to the dosing ofthe controlled release formulations of the invention means that thecontrolled release formulation is orally administered before the patientgoes to bed in the evening, generally between about 8 p.m. and 12 p.m.

The term “therapeutically effective reduction” when used herein is meantto signify that blood glucose levels are reduced by approximately thesame amount as an immediate release reference standard (e.g.,GLUCOPHAGE®) or more, when the controlled release dosage form is orallyadministered to a human patient on a once-a-day basis.

The term “sustained release” and “controlled release” are usedinterchangeably in this application and are defined for purposes of thepresent invention as the release of the drug from the dosage form atsuch a rate that when a once-a-day dose of the drug is administered inthe sustained release or controlled-release form, blood (e.g., plasma)concentrations (levels) of the drug are maintained within thetherapeutic range but below toxic levels over a period of time fromabout 12 to about 24 hours. When the drug used in the present inventionis metformin (preferably metformin hydrochloride) the controlled releasesolid oral dosage form containing such drug is also referred to as“Metformin XT.”

The term “C_(max)” is the highest plasma concentration of the drugattained within the dosing interval, i.e., about 24 hours.

The term “C_(min)” is the minimum plasma concentration of the drugattained within the dosing interval, i.e. about 24 hours.

The term “C_(avg)” as used herein, means the plasma concentration of thedrug within the dosing interval, i.e. about 24-hours, and is calculatedas AUC/dosing interval.

The term “T_(max)” is the time period which elapses after administrationof the dosage form at which the plasma concentration of the drug attainsthe highest plasma concentration of drug attained within the dosinginterval (i.e., about 24 hours).

The term “AUC” as used herein, means area under the plasmaconcentration-time curve, as calculated by the trapezoidal rule over thecomplete 24-hour interval.

The term “steady state” means that the blood plasma concentration curvefor a given drug does not substantially fluctuate after repeated dosesto dose of the formulation.

The term “single dose” means that the human patient has received asingle dose of the drug formulation and the drug plasma concentrationhas not achieved steady state.

The term “multiple dose” means that the human patient has received atleast two doses of the drug formulation in accordance with the dosinginterval for that formulation (e.g., on a once-a-day basis). Patientswho have received multiple doses of the controlled release formulationsof the invention may or may not have attained steady state drug plasmalevels, as the term multiple dose is defined herein.

The term “a patient” means that the discussion (or claim) is directed tothe pharmacokinetic parameters of an individual patient and/or the meanpharmacokinetic values obtained from a population of patients, unlessfurther specified.

The term “mean”, when preceding a pharmacokinetic value (e.g. meanT_(max)) represents the arithmetic mean value of the pharmacokineticvalue taken from a population of patients unless otherwise specified(e.g. geometric mean).

The term “Degree of Fluctuation” is expressed as(C_(max)−C_(min))/C_(avg).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the relative bioavailability of the metforminXT formulation of Example 2 to GLUCOPHAGE® for Clinical Study 2.

FIG. 2 is a graph showing the relative bioavailability of the metforminXT formulation of Example 1 (500 mg) to GLUCOPHAGE(D for Clinical Study3.

FIG. 3 is a graph showing the difference in plasma concentration-timeprofiles of metformin in eight healthy volunteers between Day 1 and Day14 dosing following oral administration of the metformin XT formulationof Example 1, 4×500 mg q.d. for 14 days for Clinical Study 4.

FIG. 4 is a graph showing the mean plasma profiles and values ofpharmacokinetic parameters of the metformin XT formulation of Example 3for Clinical Study 5.

FIG. 5 is a graph showing the mean plasma glucose concentration-timeprofiles after 4 weeks of treatment with the metformin XT formulation ofExample 3 and GLUCOPHAGE® for Clinical Study 5.

FIG. 6 is a graph showing the dissolution profile of a 500 mg controlledrelease metformin formulation of Example 1 of the present invention.

FIG. 7 is a graph showing the dissolution profile of a 850 mg controlledrelease metformin formulation of Example 2 of the present invention.

FIG. 8 is a graph showing the dissolution profile of a 1000 mgcontrolled release metformin formulation of Example 3 of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

The term antihyperglycemic drugs as used in this specification refers todrugs that are useful in controlling or managing noninsulin-dependentdiabetes mellitus (NIDDM). Preferably, the antihyperglycemic drug is abiguanide such as metformin or buformin or a pharmaceutically acceptablesalt thereof such as metformin hydrochloride.

It has surprisingly been found that when biguanides such as metforminare administered orally in a controlled release dosage form suitable foronce-a-day dosing in the “fed” state, preferably at dinner, thebioavailability is improved as compared to the administration of thecontrolled release dosage form in the “fasted” state. This is incontrast to GLUCOPHAGE®, which exhibits opposite characteristics. Inaccordance with the methods and dosage forms of the present invention,it has been determined that the patients suffering from NIDDM achieveimproved results (e.g., lowered blood glucose levels) than GLUCOPHAGE®administered according to accepted protocols, e.g., on a twice-a-daybasis.

The methods and dosage forms of the invention provide the furtheradvantage in that when dosed at dinnertime, the controlled releaseformulations of the invention provide a T_(max) (from 5.5 to 7.5 hours)after oral administration (which T_(max) is delayed relative to thereference standard, GLUCOPHAGE®, such that the level of drug is greatestat the time when human patients are manufacturing glucose at highestlevels. Gluconeogenesis is well known to those skilled in the art to begreatest at night. Thus, in accordance with the invention, the T_(max)of the drug occurs for example between 11:30 p.m. and 1:30 a.m., basedon a dose administered at 6:00 p.m. Likewise, such administration of thedosage form provides lower drug levels during the day (e.g. theafternoon) when gluconeogenesis is lower than at night. Also, theinvention preferably provides the added benefit of lowering insulinlevels. Insulin is considered a risk factor in NIDDM, in and of itself,for cardiovascular disease.

In comparison to a twice-daily dose of the reference standard(GLUCOPHAGE®), the plasma levels of metformin are preferably lower inthe afternoon. This is an advantage particularly in patients who areunder concomitant therapy with one or more additional antidiabeticagents, such as for example, a sulfonylurea. It is known in the art thatto date approximately 60% of patients being treated with metformin arealso being treated with at least one additional antidiabetic agent (suchas a sulfonylurea). Sulfonylureas can possibly cause hypoglycemia,whereas metformin cannot, so there is a benefit to having lowermetformin levels in the blood during the afternoon due to the potentialfor the patient to have hypoglycemia.

Accordingly, the present invention also includes a method of treatinghuman patients with NIDDM comprising administering on a once-a-day basisa therapeutically effective dose of metformin in a controlled-releaseoral dosage form (“Metformin XT”), in combination with administering aneffective amount of a sulfonylurea. In preferred embodiments, metforminis provided by a controlled release dosage form comprising metformin ora pharmaceutically acceptable salt thereof, the dosage form being usefulfor providing a once-a-day oral administration of the drug, wherein thedosage form provides a mean time to maximum plasma concentration(T_(max)) of metformin from 5.5 to 7.5 hours after administration.

In certain embodiments, the combination therapy may be provided asfollows. If patients do not respond to four weeks of the maximum dose ofMetformin XT (2500 mg/day) monotherapy, a sulfonylurea may be graduallyadded while maintaining the maximum dose of Metformin XT, even if priorprimary or secondary failure to a sulfonylurea has occurred. Examples ofthe sulfonylurea include glyburide (glibenclamid), chloropropamide,tolbutamide, glipizide, acetohexamide and tolazamide. Although MetforminXT is preferably administered on once-a-day basis, the sulfonylurea maybe administered in a different dosage form and at a different frequency.

With concomitant Metformin XT and sulfonylurea therapy, the desiredcontrol of blood glucose may be obtained by adjusting the dose of eachdrug.

In certain embodiments, the foregoing objectives are met by a controlledrelease dosage form comprising:

-   -   (a) a core comprising:        -   (i) an antihyperglycemic drug;        -   (ii) optionally a binding agent; and        -   (iii) optionally an absorption enhancer;    -   (b) a membrane coating surrounding the core; and    -   (c) at least one passageway in the membrane.

The binding agent may be any conventionally known pharmaceuticallyacceptable binder such as polyvinyl pyrrolidone, hydroxypropylcellulose, hydroxyethyl cellulose, ethylcellulose, polymethacrylate,waxes and the like. Mixtures of the aforementioned binding agents mayalso be used. The preferred binding agents are water soluble such aspolyvinyl pyrrolidone having a weight average molecular weight of 25,000to 3,000,000. The binding agent comprises approximately about 0 to about40% of the total weight of the core and preferably about 3% to about 15%of the total weight of the core.

The core may optionally comprise an absorption enhancer. The absorptionenhancer can be any type of absorption enhancer commonly known in theart such as a fatty acid, a surfactant, a chelating agent, a bile saltor mixtures thereof. Examples of some preferred absorption enhancers arefatty acids such as capric acid, oleic acid and their monoglycerides,surfactants such as sodium lauryl sulfate, sodium taurocholate andpolysorbate 80, chelating agents such as citric acid, phytic acid,ethylenediamine tetraacetic acid (EDTA) and ethylene glycol-big(B-aminoethyl ether-N,N,N,N-tetraacetic acid (EGTA). The core comprisesapproximately 0 to about 20% of the absorption enhancer based on thetotal weight of the core and most preferably about 2% to about 10% ofthe total weight of the core.

In this embodiment, the core which comprises the antihyperglycemic drug,the binder which preferably is a pharmaceutically acceptable watersoluble polymer and the absorption enhancer is preferably formed by wetgranulating the core ingredients and compressing the granules with theaddition of a lubricant into a tablet on a rotary press. The core mayalso be formed by dry granulating the core ingredients and compressingthe granules with the addition of a lubricant into tablets or by directcompression.

Other commonly known excipients may also be included into the core suchas lubricants, pigments or dyes.

The homogeneous core is coated with a membrane, preferably a polymericmembrane to form the controlled release tablet of the invention. Themembrane can be a semipermeable membrane by being permeable to thepassage of external fluid such as water and biological fluids and beingimpermeable to the passage of the antihyperglycemic drug in the core.Materials that are useful in forming the membrane are cellulose esters,cellulose diesters, cellulose triesters, cellulose ethers, celluloseester-ether, cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, cellulose acetate propionate, and cellulose acetatebutyrate. Other suitable polymers are described in U.S. Pat. Nos.3,845,770, 3,916,899, 4,008,719, 4,036,228 and 4,11210 which areincorporated herein by reference. The most preferred membrane materialis cellulose acetate comprising an acetyl content of 39.3 to 40.3%,commercially available from Eastman Fine Chemicals.

In an alternative embodiment, the membrane can be formed from theabove-described polymers and a flux enhancing agent. The flux enhancingagent increases the volume of fluid imbibed into the core to enable thedosage form to dispense substantially all of the antihyperglycemic drugthrough the passageway and/or the porous membrane. The flux enhancingagent can be a water soluble material or an enteric material. Someexamples of the preferred materials that are useful as flux enhancersare sodium chloride, potassium chloride, sucrose, sorbitol, mannitol,polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose,hydroxypropyl methycellulose, hydroxyprophy methycellulose phthalate,cellulose acetate phthalate, polyvinyl alcohols, methacrylic acidcopolymers and mixtures thereof. The preferred flux enhancer is PEG 400.

The flux enhancer may also be a drug that is water soluble such asmetformin or its pharmaceutically acceptable salts or a drug that issoluble under intestinal conditions. If the flux enhancer is a drug, thepresent dosage form has the added advantage of providing an immediaterelease of the drug which is selected as the flux enhancer.

The flux enhancing agent comprises approximately 0 to about 40% of thetotal weight of the coating, most preferably about 2% to about 20% ofthe total weight of the coating. The flux enhancing agent dissolves orleaches from the membrane to form paths in the membrane for the fluid toenter the core and dissolve the active ingredient.

In alternate embodiments, the membrane may also be formed with commonlyknown excipients such as a plasticizer. Some commonly known plasticizersinclude adipate, azelate, enzoate, citrate, stearate, isoebucate,sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butylcitrate, citric acid esters, and those described in the Encyclopedia ofPolymer Science and Technology, Vol. 10 (1969), published by John Wiley& Sons. The preferred plasticizers are triacetin, acetylatedmonoglyceride, grape seed oil, olive oil, sesame oil,acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol,diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate,diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate,tributylcitrate, glyceroltributyrate, and the like. Depending on theparticular plasticizer, amounts of from 0 to about 25%, and preferablyabout 2% to about 15% of the plasticizer can be used based upon thetotal weight of the coating.

As used herein the term passageway includes an aperture, orifice, bore,hole, weakened area or an erodible element such as a gelatin plug thaterodes to form an osmotic passageway for the release of theantihyperglycemic drug from the dosage form. A detailed description ofthe passageway can be found in U.S. Pat. Nos. such as U.S. Pat. Nos.3,845,770, 3,916,899, 4,034,758, 4,063,064, 4,077,407, 4,088,864,4,783,337 and 5,071,607 (the disclosures of which are herebyincorporated by reference).

In certain embodiments, the passageway is formed by laser drilling. Inother embodiments, the passageway is formed by making an indentationonto the core prior to the membrane coating to form a weakened area ofthe membrane at the point of the indentation. In preferred embodimentsof the invention, the dosage form contains two passageways in orderprovide the desired pharmacokinetic parameters of the formulation.

Generally, the membrane coating around the core will comprise from about1% to about 7%, preferably about 1.5% to about 3%, based on the totalweight of the core and coating.

The term “membrane” means a membrane that is permeable to both aqueoussolutions or bodily fluids and to the active drug or pharmaceuticalingredient (e.g. the formulations of Examples 1-3). Thus, the membraneis porous to drug and, in a preferred embodiment, drug is releasedthrough the hole or passageway and through the porous membrane insolution or in vivo. The term “membrane” also generically encompassesthe term “semipermeable membrane” as heretofore defined.

In an alternative embodiment, the dosage form of the present inventionmay also comprise an effective amount of the antihyperglycemic drug thatis available for immediate release. The effective amount ofantihyperglycemic drug for immediate release may be coated onto themembrane of the dosage form or it may be incorporated into the membrane.

In certain preferred embodiments of the invention where the dosage formis prepared in accordance with the above, the dosage form will have thefollowing composition: INGREDIENT Preferred Most Preferred CORE: Drug50-98% 75-95% Binder  0-40%  3-15% Absorption Enhancer  0-20%  2-10%COATING: Membrane Polymer 50-99% 75-95% Flux Enhancer  0-40%  2-20%Plasticizer 0-25% or 0-30%  2-15%

The dosage forms prepared according to certain embodiments of thepresent invention preferably exhibit the following dissolution profilewhen tested in a USP type 2 apparatus at 75 rpms in 900 ml of simulatedintestinal fluid (pH 7.5 phosphate buffer) and at 37° C.: Time (Hours)Preferred Most Preferred 2  0-30% 0-15% or 0-25% 4 10-45% 20-40% 830-90% 45-90% 12 NTL 50% NTL 60% 16 NTL 60% NTL 70% 20 NTL 70% NTL 80%NTL = Not less than

In the preparation of the tablets of the invention, various conventionalwell known solvents may be used to prepare the granules and apply theexternal coating to the tablets of the invention. In addition, variousdiluents, excipients, lubricants, dyes, pigments, dispersants, etc.which are disclosed in Remington's Pharmaceutical Sciences, 1995 Editionmay be used to optimize the formulations of the invention.

Other controlled release technologies known to those skilled in the artcan be used in order to achieve the controlled release formulations ofthe present invention, i.e., formulations which provide a mean T_(max)of the drug and/or other pharmacokinetic parameters described hereinwhen orally administered to human patients. Such formulations can bemanufactured as a controlled oral formulation in a suitable tablet ormultiparticulate formulation known to those skilled in the art. Ineither case, the controlled release dosage form may optionally include acontrolled release carrier which is incorporated into a matrix alongwith the drug, or which is applied as a controlled release coating.

An oral dosage form according to the invention may be provided as, forexample, granules, spheroids, beads, pellets (hereinafter collectivelyreferred to as “multiparticulates”) and/or particles. An amount of themultiparticulates which is effective to provide the desired dose of drugover time may be placed in a capsule or may be incorporated in any othersuitable oral form.

In certain preferred embodiments, the tablet core or multiparticulatescontaining the drug are coated with a hydrophobic material selected from(i) an alkylcellulose and (ii) a polymeric glycol. The coating may beapplied in the form of an organic or aqueous solution or dispersion. Thecoating may be applied to obtain a weight gain from about 2 to about 25%of the substrate in order to obtain a desired sustained release profile.The sustained release coatings of the present invention may also includean exit means comprising at least one passageway, orifice, or the likeas previously disclosed.

DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLE 1

A controlled release tablet containing 500 mg of metformin HCl andhaving the following formula is prepared as follows:

I. Core Ingredients Amount (mg/tab) Metformin HCl 500.0 Povidone³, USP36.0 Sodium Lauryl Sulfate 25.8 Magnesium Stearate 2.8³approximate molecular weight = 1,000,000; dynamic viscosity (10% w/vsolution at 20° C.) = 300-700 m Pa s.

(a) Granulation

The metformin HCl and sodium lauryl sulfate are delumped by passing themthrough a 40 mesh screen and collecting them in a clean,polyethylene-lined container. The povidone, K-90-F is dissolved inpurified water. The delumped metformin HCl and sodium lauryl sulfate arethen added to a top-spray fluidized bed granulator and granulated byspraying with the binding solution of povidone under the followingconditions: inlet air temperature of 50-70° C.; atomization air pressureof 1-3 bars; and spray rate of 10-100 m/min.

Once the binding solution is depleted, the granules are dried in thegranulator until the loss on drying is less than 2%. The dried granulesare passed through a Comil equipped with the equivalent of an 18 meshscreen.

(b) Tableting

The magnesium stearate is passed through a 40 mesh stainless steelscreen and blended with the metformin HCl granules for approximatelyfive (5) minutes. After blending, the granules are compressed on arotary press fitted with 15/32″ round standard concave punches.

(c) Seal Coating (Optional)

The core tablet is seal coated with an Opadry material or other suitablewater-soluble material by first dissolving the Opadry material,preferably Opadry Clear (YS-1-7006), in purified water. The Opadrysolution is then sprayed onto the core tablet using a pan coater underthe following conditions: exhaust air temperature of 38-42° C.;atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min. TheOpadry Clear of the coating constitutes about 11.5 mg/tablet.

II. Sustained Release Coating Ingredients Amount (mg/tablet) CelluloseAcetate (398-10)² 21.5 Triacetin 1.3 PEG 400 2.5²acetyl content 39.3-40.3%

The cellulose acetate is dissolved in acetone while stirring with ahomogenizer. The polyethylene glycol 400 and triacetin are added to thecellulose acetate solution and stirred until a clear solution isobtained. The tablet is coated by spraying the clear coating solutiononto the seal coated tablets in a fluidized bed coater employing thefollowing conditions: product temperature of 16-22° C.; atomizationpressure of approximately three bars; and spray rate of 120-150 ml/min.

(d) Laser Drilling

The coated tablets were laser drilled two holes (one hole on each sideof the tablet).

EXAMPLE 2

A controlled release tablet containing 850 mg of metformin HCl andhaving the following formula is prepared as follows:

I. Core Ingredients Amount (mg/tab) Metformin HCl 850.0 Povidone³, USP61.1 Sodium Lauryl Sulfate 43.9 Magnesium Stearate 4.8³approximate molecular weight = 1,000,000; dynamic viscosity (10% w/vsolution at 20° C.) = 300-700 m Pa s.

(a) Granulation

The metformin HCl and sodium lauryl sulfate are delumped by passing themthrough a 40 mesh screen and collecting them in a clean,polyethylene-lined container. The povidone, K-90-F is dissolved inpurified water. The delumped metformin HCl and sodium lauryl sulfate arethen added to a top-spray fluidized bed granulator and granulated byspraying with the binding solution of povidone under the followingconditions: inlet air temperature of 50-70° C.; atomization air pressureof 1-3 bars; and spray rate of 10-100 ml/min.

Once the binding solution is depleted, the granules are dried in thegranulator until the loss on drying is less than 2%. The dried granulesare passed through a Comil equipped with the equivalent of an 18 meshscreen.

(b) Tableting

The magnesium stearate is passed through a 40 mesh stainless steelscreen and blended with the metformin HCl granules for approximatelyfive (5) minutes. After blending, the granules are compressed on arotary press fitted with 15/32″ round standard concave punches.

(c) Seal Coating (Optional)

The core tablet is seal coated with an Opadry material or other suitablewater-soluble material by first dissolving the Opadry material,preferably Opadry Clear (YS-1-7006), in purified water. The Opadrysolution is then sprayed onto the core tablet using a pan coater underthe following conditions: exhaust air temperature of 38-42° C.;atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min. TheOpadry Clear of the coating constitutes about 11.5 mg/tablet.

II. Sustained Release Coating Ingredients Amount (mg/tablet) CelluloseAcetate (398-10)² 24.0 Triacetin 1.4 PEG 400 2.8²acetyl content 39.3-40.3%

The cellulose acetate is dissolved in acetone while stirring with ahomogenizer. The polyethylene glycol 400 and triacetin are added to thecellulose acetate solution and stirred until a clear solution isobtained. The tablet is coated by spraying the clear coating solutiononto the seal coated tablets in a fluidized bed coater employing thefollowing conditions: product temperature of 16-22° C.; atomizationpressure of approximately three bars; and spray rate of 120-150 ml/min.

(d) Laser Drilling

The coated tablets were laser drilled two holes (one hole on each sideof the tablet).

EXAMPLE 3

A controlled release tablet containing 1000 mg of metformin HCl andhaving the following formula is prepared as follows:

I. Core Ingredients Amount (mg/tablet) Metformin HCl 1000.0 Povidone³,USP 71.9 Sodium Lauryl Sulfate 51.7 Magnesium Stearate 5.6³approximate molecular weight = 1,000,000; dynamic viscosity (10% w/vsolution at 20° C.) = 300-700 m Pa s.

(a) Granulation

The metformin HCl and sodium lauryl sulfate are delumped by passing themthrough a 40 mesh screen and collecting them in a clean,polyethylene-lined container. The povidone, K-90-F is dissolved inpurified water. The delumped metformin HCl and sodium lauryl sulfate arethen added to a fluidized bed granulator and granulated by spraying withthe binding solution of povidone under the following conditions: inletair temperature of 50-70° C.; atomization air pressure of 1-3 bars; andspray rate of 10-100 ml/min.

Once the binding solution is depleted, the granules are dried in thegranulator until the loss on drying is less than 2%. The dried granulesare passed through a Comil equipped with a screen equivalent to 18 mesh.

(b) Tableting

The magnesium stearate is passed through a 40 mesh stainless steelscreen and blended with the metformin HCl granules for approximatelyfive (5) minutes. After blending, the granules are compressed on arotary press fitted with ½″ round standard concave punches.

(c) Seal Coating (Optional)

The core tablet is seal coated with an Opadry material or other suitablewater-soluble material by first dissolving the Opadry material,preferably Opadry Clear (YS-1-7003), in purified water. The Opadrysolution is then sprayed onto the core tablet using a pan coater underthe following conditions: exhaust air temperature of 38-42° C.;atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min. Thecore tablet is coated with the sealing solution until the tablet iscoated with 23.0 mg/tablet of the Opadry material.

II. Sustained Release Coating Ingredients Amount (mg/tablet) CelluloseAcetate (398-10)² 19.0 Triacetin 1.1 PEG 400 2.2²acetyl content 39.3-40.3%

The cellulose acetate is dissolved in acetone while stirring with ahomogenizer. The polyethylene glycol 400 and triacetin are added to thecellulose acetate solution and stirred until a clear solution isobtained. The tablet is coated by spraying the clear coating solutiononto the seal coated tablets in a fluidized bed coater employing thefollowing conditions: product temperature of 16-22° C.; atomizationpressure of approximately three bars; and spray rate of 120-150 m/min.

(d) Laser Drilling

The coated tablets were laser drilled two holes (one hole on each sideof the tablet).

(e) Color Coating (Optional)

Subsequent to the sustained release coating, the laser drilled tablet iscoated with a color coating using Opadry White (24 mg/tablet) and waxedwith Candelilla wax powder (0.4 mg/tablet).

Clinical Studies Study 1

In study 1, a total of twelve (12) healthy subjects (six males, sixfemales) were randomized to receive either a single oral dose ofmetformin XT, 850 mg, prepared in accordance with Example 2 or b.i.d.doses of GLUCOPHAGE in assigned study periods which consisted of one ofthe following groups: Group A—metformin XT (2 x 850 mg tablets) taken atapproximately 8:00 a.m., immediately following breakfast, GroupB—metformin XT (2×850 mg tablets) taken at approximately 6:00 p.m.,immediately following dinner; and Group C—GLUCOPHAGE (1×850 mg tablet)taken at approximately 8:00 a.m., immediately following breakfast, andat approximately 6:00 p.m., immediately following dinner. Each drugadministration was separated by a washout period of seven days. In thisstudy, one male subject was removed from the study prior to Period IIdue to non-treatment-related mononucleosis. Thus, 11 (five males and sixfemales) subjects completed the study.

For metformin XT, plasma samples were obtained from subjects at 0(predose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 24 hour(s) afterdosing. For GLUCOPHAGE, plasma samples were obtained from subjects at 0(predose), 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22,and 24 hour(s) after the first dose in the morning. Plasmaconcentrations of metformin were determined using a validated HPLCmethod. The lower quantitation limit of this method is 10 ng/ml. Meanplasma concentration-time profiles are shown in FIG. 1 and mean valuesof pharmacokinetic parameters of metformin obtained from this study arepresented in Table 1. TABLE 1 Mean (±SD, n = 11) values ofpharmacokinetic parameters of metformin (Example 2) in 11 healthysubjects (metformin XT, 2 × 850 mg q.d. or GLUCOPHAGE, 1 × 850 mgb.i.d.) Geometric AUC_(0-∞) C_(max) T_(lag) t_(1/2) Mean Ratio*Treatment (ng-hr/ml) (ng/ml) T_(max) (hr.) (hr) (hr) AUC_(0-∞) C_(max)Metformin XT 18156 2045 6 0.18 4.4 1.00 1.36 after breakfast  (4183) (567) (2) (0.40) (0.7) Metformin XT 18277 1929 7 0.09 3.6 1.02 1.32after dinner  (2961)  (333) (2) (0.30) (0.8) GLUGOPHAGE 18050 1457 5 0  3.5 — —  (3502)  (217) (3) (0)   (0.9)*Ratio = Metformin XT/GLUCOPHAGE

As shown in FIG. 1 and Table 1, when metformin XT was administeredimmediately after either breakfast or dinner, the relativebioavailability of metformin XT formulation to GLUCOPHAGE isapproximately 100%.

The results of study 1 were used to calculate the approximate degree offluctuation (C_(max)−C_(min)/C_(avg)) of the formulations.

The C_(max) was directly obtained from the study (see Table 1). TheC_(avg) was obtained by dividing the AUC value by the dosing interval,i.e. 24 hours. The value for C_(min) was extrapolated from FIG. 1.

The results are set forth in Table 2 below: TABLE 2 Mean (±SD, n = 12)values of pharmacokinetic parameters of metformin XT in 12 healthysubjects (metformin XT, 2 × 850 mg q.d. and GLUCOPHAGE, 850 mg b.i.d.)AUC_(0-∞) Degree (ng- C_(max) C_(min) C_(avg) of Fluc- Treatment hr/ml)(ng/ml) (ng/ml) (ng/ml) tuation Metformin XT 18156 2045 143 756 2 . . .after breakfast  (4183)  (567) 51 Metformin XT 18277 1929 107 761 2.39after dinner  (2961)  (333) GLUCOPHAGE 18050 1457 214 752 1.65  (3502) (217) (at 24 hours) 393 752 1.41 (between doses)

As shown in FIG. 1 and Table 2, a single administration of the metforminXT formulation provides a higher mean fluctuation index in the plasmathan a substantially equal dose of Glucophage administered as two equaldivided doses, one divided dose at the start of the dosing interval andthe other divided dose administered 12 hours later.

Study 2

The study design of Study 2 is the same as Study 1 except for theformulation and the dose (4×500 mg q.d., total dose 2000 mg, formetformin XT prepared according to Example 1 and 2×500 mg b.i.d., totaldose 2000 mg, for GLUCOPHAGE in the second study). In this study, 12healthy volunteers (five males and seven females) were randomized toreceive treatments and completed the study. Mean plasmaconcentration-time profiles and mean values of pharmacokineticparameters of metformin obtained from this study are presented in FIG. 2and Table 3.

As shown in FIG. 2 and Table 3, when the metformin XT formulation (500mg) was administered immediately after dinner, the relativebioavailability of this formulation to GLUCOPHAGE is approximately 100%,while the mean C_(max) value is about the same. The relativebioavailability of metformin XT, however, is approximately 80% whenadministered immediately after breakfast. A prolonged profile, togetherwith later T_(max) and similar C_(max) of metformin followingadministration of metformin XT immediately after dinner compared toGLUCOPHAGE indicated that metformin was released in vivo in a sustainedfashion (FIG. 2). TABLE 3 Mean (±SD, n = 12) values of pharmacokineticparameters of metformin of Example 1 in 12 healthy subjects (metforminXT, 4 × 500 mg q.d. or GLUCOPHAGE, 2 × 500 mg b.i.d.) AUC_(0-∞)Geometric (ng- C_(max) T_(lag) t_(1/2) Mean Ratio* Treatment hr/ml)(ng/ml) T_(max) (hr) (hr) (hr) AUC_(0-∞) C_(max) Metformin XT 17322 21275 0   6.1 0.80 1.15 after breakfast  (4984)  (545) (1) (0)   (1.8)Metformin XT 20335 2053 7 0.08 3.9 0.96 1.12 after dinner  (4360)  (447)(2) (0.29) (0.6) GLUCOPHAGE 21181 1815 4 0   3.6 — —  (4486)  (302) (3)(0)   (0.8)*Ratio = Metformin XT/GLUCOPHAGE

The results of study 2 were used to calculate the approximate degree offluctuation of the formulations in accordance with the calculations usedin study 1 (using FIG. 2 to obtain the extrapolated value for C_(min)).

The results are set forth in Table 4 below: TABLE 4 Mean (±SD, n = 12)values of pharmacokinetic parameters of metformin XT in 12 healthysubjects (metformin XT, 4 × 500 mg q.d. and GLUCOPHAGE, 2 × 500 mgb.i.d.) AUC_(0-∞) Degree (ng- C_(max) C_(min) C_(avg) of Fluc- Treatmenthr/ml) (ng/ml) (ng/ml) (ng/ml) tuation Metformin XT 17322 2127 143 7212.9 after breakfast  (4984)  (545) Metformin XT 20335 2053 143 847 2.25after dinner  (4360)  (447) GLUCOPHAGE 21181 1815 214 882 1.8  (4486) (302) (at 24 hours) 357 882 1.65 (between doses)

As shown in FIG. 2 and Table 4, a single administration of the metforminXT formulation provides a higher mean fluctuation index in the plasmathan an equivalent dose of Glucophage administered as two equal divideddoses, one divided dose at the start of the dosing interval and theother divided dose administered 12 hours later.

Study 3

In Study 3, a multiple-dose, open-label, one-period study was conductedto evaluate the short-term tolerability and steady-statepharmacokinetics of the 500 mg metformin XT formulation used in Study 2.In this study, eight healthy volunteers (four males and four females)were randomized to receive 2000 mg of metformin XT (4×500 mg tablets) atapproximately 6:00 p.m., immediately following dinner, for 14 days.

Blood samples were obtained from each subject at 0 (predose), 1, 2, 3,4, 5, 6, 8, 10, 12, 14, 16 and 24 hour(s) following the first dose onDay 1 and at 0 (predose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 38and 48 hour(s) following the last dose on Day 14. Blood samples werealso drawn from each subject immediately prior to dosing on Days 10-13.Urine samples were collected from each subject at the following timeintervals: six hours prior to the first dose; 0-6, 6-12 and 12-24 hoursafter the first dose; and 0-6, 6-12, 12-24 and 24-48 hours after thelast dose.

Mean plasma profiles and values of pharmacokinetic parameters ofmetformin are presented in Table 5 below: TABLE 5 Mean PharmacokineticParameters (Example 1) C_(max) T_(max) AUC_(0-24 hr (ng·hr/ml)) Day 1Mean 2435 6.9 22590 SD 630 1.9 3626 Day 14 Mean 2288 6.9 24136 SD 7362.5 7996

Following oral administration of metformin XT, 4×500 mg q.d., for 14days, there was little or no difference in plasma concentration-timeprofiles of metformin in eight healthy volunteers between Day 1 and Day14 dosing (FIG. 3). On average, trough plasma concentrations ofmetformin were nearly constant, ranging from 188.8 to 205.1 ng/ml onDays 10-14, indicating that the steady state of metformin was attainedrapidly. The mean accumulation ratio was 1.01, indicating that theonce-daily dose regimen of metformin XT results in no accumulation.

Following oral administration of a single dose (4×500 mg) of metforminXT, approximately 31% of the dose was excreted in the urine within thefirst 24 hours. On average, the renal clearance of metformin was 366ml/min. A slightly higher renal clearance (454 ml/min) was found aftermultiple-dose administration of 4×500 mg q.d. of metformin XT.

Gastrointestinal symptoms (diarrhea, nausea, vomiting, abdominalbloating, flatulence and anorexia) are the most common adverse reactionsto GLUCOPHAGE. In controlled trials, GLUCOPHAGE was started at low,nontherapeutic doses and gradually titrated to higher doses. In spite ofthis gradual titration, GLUCOPHAGE was discontinued due togastrointestinal reactions in approximately 4% of patients. In contrast,in the multiple-dose study, metformin XT begun at a therapeutic initialdose of 2000 mg once daily with dinner was well tolerated by all healthyvolunteers. Diarrhea and nausea were the most common gastrointestinalreactions probably or possibly related to metformin XT. These reactions,however, were either mild or moderate. This suggests that it may bepossible to initiate metformin XT treatment with effective doses ratherthan using the slow titration from non-therapeutic doses required forGLUCOPHAGE.

Study 4

Study 4 was a study designed to evaluate the safety, tolerability,pharmacokinetics and pharmacodynamics of metformin XT compared toGLUCOPHAGE after multiple-dose treatment in patients with NIDDM.Metformin XT tablets prepared according to Example 3 were used in thisstudy. This study had a single-center, randomized, two-way crossoverdesign. A total of 24 NIDDM patients who were on a stable dose ofGLUCOPHAGE, between 1000 and 2550 mg/day, for at least 12 weeks wereselected for the study. A Pretreatment Period of at least 3 weekspreceded randomization to study treatment. At the start of thePretreatment Period, all patients stopped taking any other hypoglycemicagents besides GLUCOPHAGE, and the GLUCOPHAGE dose was adjusted to 1000mg b.i.d. (with breakfast and with dinner). Following the pretreatmentperiod, patients began Treatment Period I, which lasted 4 weeks. DuringPeriod I, a total of 12 patients were randomized to receive two 1000-mgmetformin XT tablets q.d. (immediately after dinner), at approximately6:00 p.m., and 12 were randomized to receive one 1000-mg GLUCOPHAGEtablet b.i.d. (immediately after breakfast and immediately afterdinner). Immediately following Period I, each patient was switched tothe alternate medication for 4 weeks in Period II. There was no washoutbetween treatment periods.

Plasma metformin concentrations were determined over a 24-hour period atthe end of Treatment Periods I and II as follows: immediately prior todosing and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 15, 16, 17, 18, 19, 20,22, and 24 hours after the evening dose. One subject withdrew from thestudy for personal reasons after two weeks of treatment in TreatmentPeriod I, thus pharmacokinetic data were obtained from 23 patients.

Mean plasma profiles and values of pharmacokinetic parameters ofmetformin are presented in FIG. 4 and Table 6. As shown in FIG. 4 andTable 6, when metformin XT was administered immediately after dinner,the bioavailability of metformin XT relative to GLUCOPHAGE at steadystate is close to 100%. Although the dose of metformin XT was twice aslarge as the dose of GLUCOPHAGE at dinner, the mean C_(max) value wasonly 32% higher. TABLE 6 Mean (± SD) values of pharmacokineticparameters of metformin of Example 3 in 23 NIDDM patients (metformin XT,2 × 1000 mg q.d. with dinner or GLUCOPHAGE, 1 × 1000 mg b.i.d.)AUC_(0-24 hr) C_(max) T_(max) T_(lag) t_(1/2) Geometric Mean Ratio*Treatment (ng · hr/ml) (ng/ml) (hr) (hr) (hr) AUC_(0-24 hr) C_(max)Metformin XT 26818 2849 6 0 5.4 0.96 1.32 after dinner  (7052)  (797)(2) (0) GLUCOPHAGE 27367 2131 14  0 4.4 — —  (5759)  (489) (6) (0)*Ratio = Metformin XT/GLUCOPHAGE

When the metformin XT was administered immediately after dinner, thebioavailability of metformin XT relative to GLUCOPHAGE at steady statewas close to 100%. However, when metformin XT was administeredimmediately after breakfast, the corresponding relative bioavailabilityof metformin XT was approximately 80%. The safety profile of metforminXT, 2000 mg given once daily either after dinner or after breakfast wascomparable to that of an equal dose of GLUCOPHAGE given b.i.d. Theefficacy profile of metformin XT, 2000 mg given once daily after dinnerwas similar to that of an equal dose of GLUCOPHAGE given b.i.d. Theefficacy of metformin XT, 2000 mg given once daily after breakfast,however, appeared to be comparable to or slightly less than that ofGLUCOPHAGE given b.i.d.

While certain preferred and alternative embodiments of the inventionhave been set forth for purposes of disclosing the invention,modifications to the disclosed embodiments may occur to those who areskilled in the art. Accordingly, the appended claims are intended tocover all embodiments of the invention and modifications thereof whichdo not depart from the spirit and scope of the invention.

1-42. (canceled)
 43. A controlled release oral dosage form for thereduction of serum glucose levels in human patients with NIDDM,comprising a core comprising metformin or a pharmaceutically acceptablesalt thereof and a membrane coating surrounding said core, said dosageform being suitable for providing once-a-day oral administration of themetformin or pharmaceutically acceptable salt thereof, wherein thedosage form provides a mean maximum plasma concentration (C_(max)) ofmetformin from about 1500 ng/ml to about 3000 ng/ml, based onadministration of a 2000 mg once-a-day dose of metformin.
 44. Thecontrolled release oral dosage form of claim 43, which provides a meanmaximum plasma concentration (C_(max)) of metformin from about 750 ng/mlto about 1500 ng/ml upon administration of a 1000 mg once-a-day dose ofmetformin.
 45. The controlled release oral dosage form of claim 43,which provides a mean maximum plasma concentration (C_(max)) ofmetformin from about 1125 ng/ml to about 2250 ng/ml upon administrationof a 1500 mg once-a-day dose of metformin.
 46. The controlled releaseoral dosage form of claim 43, which provides a mean maximum plasmaconcentration (C_(max)) of metformin from about 1875 ng/ml to about 3750ng/ml upon administration of a 2500 mg once-a-day dose of metformin. 47.The controlled release oral dosage form of claim 43, wherein said corefurther comprises a binding agent.
 48. The controlled release oraldosage form of claim 47, wherein said core further comprises anabsorption enhancer.
 49. The controlled release oral dosage form ofclaim 43, further comprising a passageway in the membrane.
 50. Thecontrolled release oral dosage form of claim 43, wherein said membranecomprises a polymer selected from the group consisting of celluloseesters, cellulose diesters, cellulose triesters, cellulose ethers,cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, cellulose acetate propionate, and cellulose acetate butyrate51. The controlled release oral dosage form of claim 50, wherein saidmembrane further comprises a plasticizer.
 52. A controlled release oraldosage form for the reduction of serum glucose levels in human patientswith NIDDM, comprising a plurality of multiparticulates comprisingmetformin or a pharmaceutically acceptable salt thereof and a controlledrelease material, said dosage form being suitable for providingonce-a-day oral administration of the metformin or pharmaceuticallyacceptable salt thereof, wherein the dosage form provides a mean maximumplasma concentration (C_(max)) of metformin from about 1500 ng/ml toabout 3000 ng/ml, based on administration of a 2000 mg once-a-day doseof metformin.
 53. The controlled release oral dosage form of claim 52,which provides a mean maximum plasma concentration (C_(max)) ofmetformin from about 750 ng/ml to about 1500 ng/ml upon administrationof a 1000 mg once-a-day dose of metformin.
 54. The controlled releaseoral dosage form of claim 52, which provides a mean maximum plasmaconcentration (C_(max)) of metformin from about 1125 ng/ml to about 2250ng/ml upon administration of a 1500 mg once-a-day dose of metformin. 55.The controlled release oral dosage form of claim 52, which provides amean maximum plasma concentration (C_(max)) of metformin from about 1875ng/ml to about 3750 ng/ml upon administration of a 2500 mg once-a-daydose of metformin.
 56. The controlled release oral dosage form of claim52, wherein said multiparticulates are selected from the groupconsisting of granules, spheroids, beads and pellets.
 57. The controlledrelease oral dosage form of claim 52, wherein said multiparticulates arecoated with the controlled release material.
 58. The controlled releaseoral dosage form of claim 52, wherein the controlled release material isselected from the group consisting of an alkylcellulose and a polymericglycol.
 59. The controlled release oral dosage form of claim 52, whereinsaid multiparticulates are incorporated into a capsule.
 60. Thecontrolled release oral dosage form of claim 43, which provides a meanAUC_(0-24hr) of metformin from about 17200 ng.hr/ml to about 33900ng.hr/ml, based on administration of a 2000 mg once-a-day dose ofmetformin.
 61. The controlled release oral dosage form of claim 60,which provides a mean AUC_(0-24hr) of metformin from about 8600 ng/ml toabout 16950 ng/ml upon administration of a 1000 mg once-a-day dose ofmetformin.
 62. The controlled release oral dosage form of claim 60,which provides a mean AUC_(0-24hr) of metformin from about 12900 ng/mlto about 25425 ng/ml upon administration of a 1500 mg once-a-day dose ofmetformin.
 63. The controlled release oral dosage form of claim 60,which provides a mean AUC_(0-24hr) of metformin from about 21500 ng/mlto about 42375 ng/ml upon administration of a 2500 mg once-a-day dose ofmetformin.
 64. The controlled release oral dosage form of claim 43,wherein said dosage form comprising said metformin or pharmaceuticallyacceptable salt thereof is contained in two formulations.
 65. Thecontrolled release oral dosage form of claim 43, wherein said core is atablet core and said membrane comprise a hydrophobic material.